Prostaglandin E.sub.2 (abbreviated as PGE.sub.2 hereafter.) has been known as a metabolite in the arachidonic acid cascade. It has been known that PGE.sub.2 has cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect of digestive peristalsis, an awaking effect, a suppressive effect of gastric acid secretion, hypotensive activity and diuretic activity etc.
In the recent studies, it was found that PGE.sub.2 receptor was divided into some subtypes which possess different physiological roles from each other. At present, four main receptor subtypes are known and they are called EP.sub.1, EP.sub.2, EP.sub.3 and EP.sub.4 (Negishi M. et al., J. Lipid Mediators Cell Signaling, 12, 379-391 (1995)).
The present inventors investigated to find new compounds which bind on each receptor specifically, so that we found that the compounds of the present invention could bind strongly on EP.sub.2 subtype receptor and achieved the present invention.
The compounds of the present invention of formula (I) possess a strong binding activity for EP.sub.2 subtype receptor. Therefore, they are useful for the prevention and/or treatment of immunological diseases (autoimmune diseases, post-transplantation graft rejection etc.), asthma, abnormal bone formation, neuronal cell death, hepatopathy, abortion, premature birth or retina neuropathy (e.g. glaucoma) etc.
Among the compounds of the present invention of formula (I), compounds which bind weakly on other receptor subtypes than EP.sub.2 and other receptors of arachidonic acid metabolites (thromboxane receptor, PGI.sub.2 receptor etc.) do not express other effects and therefore, it is probable that those compounds will be medical agents which have less side-effects.
On the other hand, many patent applications of PG derivatives are known. The following applications are mentioned for example.
(1) In the specification of JP54-115351 (i.e. U.S. Pat. No. 4,132,738), a compound of formula (A) ##STR2##
(wherein R.sup.1A and R.sup.2A are hydrogen; R.sup.3A is hydrogen or is taken together with R.sup.4A to form a methylene chain of 4 carbon atoms wherein a cycloalkyl of 6 carbon atoms inclusive is formed, or is taken together with R.sup.4A to form a bicycloalkenyl or bicycloalkyl moiety having the formula ##STR3##
(wherein pA is an integer having a value of from 0 to 1 and qA is an integer having a value of from 2 to 3 and wherein the double-bond of such bicycloalkenyl is in the qA bridge.); R.sup.4A is taken together with R.sup.3A to form a cycloalkyl, bicycloalkyl or bicycloalkenyl as defined above, or is taken together with R.sup.5A to form a methylene chain of 3 carbon atoms wherein a cycloalkyl of 4 carbon atoms inclusive is formed; R.sup.5A is hydrogen, or is taken together with R.sup.4A to form a cycloalkyl as defined above; and R.sup.6A is hydrogen or straight-chain alkyl having 8 carbon atoms.) are disclosed as having prostaglandin like activity.
(2) In the specification of JP56-92860, a compound of formula (B) ##STR4##
(wherein chlorine atom at 9-position may be attached to .alpha.- or .beta.-position; R.sup.1B is OR.sup.2B (R.sup.2B is hydrogen atom, alkyl, cycloalkyl, aryl or heterocyclic group) or NHR.sup.3B (R.sup.3B is acidic residue or hydrogen); A.sup.B is --CH.sub.2 --CH.sub.2 -- or cis-CH.dbd.CH--; B.sup.B is --CH.sub.2 --CH.sub.2 --, trans-CH.dbd.CH-- or --C.tbd.C--; W.sup.B is free or functionalized form of hydroxymethylene or free or functionalized form of --C(OH)(CH.sub.3)-- (OH may be attached to .alpha.- or .beta.-position); D.sup.B and E.sup.B are taken together to represent bond or D.sup.B is C1-10 straight-chain or branched-chain alkylene;
E.sup.B is oxygen, sulfur atom or bond;
R.sup.4B is free or functionalized form of hydroxy;
R.sup.5B is alkyl, alkyl substituted by halogen, cycloalkyl, substituted or unsubstituted aryl or heterocyclic group.)
is described.
(3) In the specification of JP58-8059, a compound of formula (C) ##STR5##
(wherein R.sup.1C is --CH.sub.2 OH, --COOR.sup.2C (R.sup.2C is hydrogen atom, alkyl which may be substituted, cycloalkyl, aryl or heterocyclic group which may be substituted by alkyl), --CONHR.sup.3C (R.sup.3C is acidic residue or R.sup.2C); A.sup.C is --CH.sub.2 --CH.sub.2 -- or cis-CH.dbd.CH--; B.sup.C is --CH.sub.2 --CH.sub.2 --, trans-CH.dbd.CH-- or --C.tbd.C--; W.sup.C is free or functionalized form of hydroxymethylene; D.sup.C and E.sup.C are taken together to form bond, or D.sup.C is C1.about.10 straight-chain or branched-chain alkylene which may be substituted by fluorine atom, E.sup.C is oxygen atom, sulfur atom, bond, --C.tbd.C--, --CR.sup.6C.dbd.CR.sup.7C --(R.sup.6C and R.sup.7C are different to represent hydrogen atom, chlorine atom or alkyl), R.sup.4C is free or functionalized form of hydroxy, R.sup.5C is hydrogen atom, halogen or alkyl which may be substituted by aryl which may be substituted, cycloalkyl, aryl or heterocyclic group which may be substituted by alkyl.) is described.